Original papers: clinical or basic research anti-cyclic citrullinated peptide antibodies - activity markers in rheumatoid arthritis

Background: Immunological abnormalities in rheumatoid arthritis (RA) imply several antibodies, among which anti-cyclic cytrullinated peptide antibodies (anti-CCP) have the highest sensitivity and specificity. Their diagnostic and prognostic value in RA is well known, although their value as markers of the disease activity has not been established yet. Objectives: The aim of this study is to evaluate the correlation between anti-CCP antibodies and RA activity which eventually leads to the best treatment of choice. Patients and Methods: 217 consecutive patients hospitalized in the Department of Internal Medicine and Rheumatology, “Sf. Maria” Clinical Hospital between 01.01-31.06 2007 were retrospectively studied. They were divided into two groups: group A-111 patients with RA (ACR criteria fulfilled) and group B-106 patients with other rheumatic diseases. The following parameters taken out of the patients, files were studied: parameters of the clinical activity of disease (C reactive protein, fibrinogen), rheumatoid factor (RF) and anti-CCP antibodies. Disease activity score (DAS) using 4 variables (number of tender joints, number of swollen joints, erythrocyte sedimentation rate and assessement of the disease activity) was also studied. Data were processed with SPSS program using linear functions, Pearson correlation coefficient and Hi2 test of interdependency. Results: The sensitivity of anti-CCP antibodies in patients with RA was 56.75%. The specificity of anti-CCP antibodies in patients with RA was 90.56%. Low seric levels of anti-CCP antibodies were also found in patients without RA, but with other conditions like: osteoarthritis, viral polyarthritis, infectious myositis and Still disease; moderate to high seric levels were found in patients with psoriatic arthritis. Significant correlations were found between anti-CCP antibodies and DAS (r=0.437), between anti-CCP and fibrinogen (r=0,32) between anti-CCP antibodies and C reactive protein (r=0,237) as well as between anti-CCP and RF (r=0, 38). Conclusions: Anti-CCP antibodies are highly specific but moderately sensitive for RA, their highest frequencies and seric levels being found in seropositive RA. Anti-CCP can be used in patients with RA not only as a diagnostic marker but also as a reliable test for assessing the activity of the disease.


nitiated as s
on as the disease sets on, thus avoiding its evolution to irreversible joint damage involved in disability and handicap of the patients.At the same time, an earl diagnosis is difficult to be made in clinical practice, as it is based on symtomatology, and, the clinical picture at the onset of the disease is incomplete and often unspecific.Therefore, the identification of a specific antibody should be used as a serological marker in the early stages of the disease.[1,2] 1 2 © 2009, Carol Davila University Foundation Many autoantibodies, present at the onset of the disease, or even before it, have been described to be of diagnostic value.They are either specific to or associated with RA, the latter being present in other diseases t

.They may be involved in the pathogenesis o
RA initiating, maintaining and modulating the immune process.The rheumatoid factor (RF) is the most common of all nonspecific autoantibodies for RA.It has been the only serological criterion approved by the American College of Rheumatologists until present and, at the same time; it is considered an accurate criterion of classification for RA.

Although these antibodies may have high sensitivity, their diagnostic value is lowered due to their low specificity and their presence in several other conditions; thus the number of autoantibody diagnosis tests should be increased.

Among specific autoantibodies for RA, anti-cyclic citrullinated peptides (CCP) antibodies are used more often than others.They are very important for the diagnosis of the disease.It is well known that their specificity for RA is very high, although their sensitivity s similar to that of rheumatoid factor (RF).The anti-CCP antibodies have recently been set as a prognostic factor for RA, because patients with high levels of these autoantiobodies have distructive and erosive forms of the disease.[4,5] 4 5

In addition, the presence of anti-CCP antibodies can be detected long before the onset of clinical manifestations (14 years) which suggests their role in the pathogenesis of RA.Therefore, the presence of anti-CCP antibodies in patients with early RA will influence the therapeutic choice and optimal time to start the treatment.[6,7,8,9] 6 7 8 9

The aim of the study is to identify a correlation between the presence and the level of anti-CCP antibodies and RA clinical and biological activity.


Patients and methods

The study was carried out retrospectively on 217 patients admitted to the Department of Internal Me icine and Rheumatology, "Sf.The study focussed on the following parametres:

-RA clinical and biological activity: DAS, C reactive protein, fibrinoge

-Presence of RF and i
s seric level -Presence of anti-CCP antibodies and their seric levels Statistical processing of data was performed with SPSS program using linear functions, Pearson correlation coefficient and Hi 2 test of interdependency.


Results

Before looking for a correlation between anti-CCP antibodies and the clinical and biological activity of RA we studied the sensitivity and specificity of these antibodies for RA.Anti-CCP antibodies tests using second generation kits are routinely performed in our clinic both for the early diagnosis and the follow-up of the disease.The tests for anti-CCP antibodies demonstrated sensitivity of 55.85% (Figure 4) and specificity of 90.56% (Fig. 5)


Although

anti-CCP antibodies specificity in RA is very high, small percentages of these a tibodies have also been identified in other pathological conditions like: osteoarthritis, infectious myositis, viral polyarthritis, Still disease (slightly positive titres), systemic lupus erythematosus, psoriatic arthritis (moderately-intensely positive titres)

The present study evaluated the relationship between an

-CCP ant
bodies and the parameters which define the activity of RA, with regard to the correlation between anti-CCP antibodies and RA clinical and biological activity.

Thus, statistically, a very significant correlation was found between anti-CCP antibodies and DAS at the level of the whole group with RA.

To go even deeper into the matter, the distribution of patients was made according to DAS into: inactive (DAS<2.6),minimally active(2.6<DAS<3.2),moderately active (3.2<DAS<5.1)and intensely active ( DAS>5.1) forms of the disease and according to the levels of anti-CCP antibodies into: absent (anti-CCP<20UI/ml), slightly positive (20<anti CCP<40 UI/ml), moderately positive (40<anti-CCP<80 UI/ml) and intensely positive (anti-CCP>80 UI/ml)

Statistically, there was a very relevant correlation between a ti-CCP antibodies and DAS (r=0,437)

The patients with intensely active RA (DAS>5.1)have the highest level of anti-CCP antibodies (anti-CCP>80 UI/ml).The correlation between these two parameters - In the group A of patients w th RA, 62 (55,8%) were anti-CCP positive and 49 (44,2%) were anti-CCP negative, while 83 (74%) were seropositive (RF positive) and 28 (26%) were seronegative (RF negative).In the subgroup of patients with RA and anti-CCP positive, 50 (80, 6% ) were seropositive (RF positive) and 12 (19, 4%) were seronegative ( RF negative).In the subgroup of patients with RA and anti-CCP negative 13 (20, 4%) were seropositive (RF positive) and 36 (79, 6%) were seronegative (RF positive).This observation confirms that patients with RA and positive RF are mainly anti-CCP positive and patients with RA and negative RF are mainly anti-CCP negative (Fig. 10).

An analysis of patients with RA accor ing to the presence or absence of RF and the level of anti-CCP antibodies (0=, 1=, 2=, 3=) shows that patients with RF have the highest level of anti-CCP antibodies.

Thus, in the subgroup of patients with seropositive RA (RF positive), 37 patients have the highest titre of anti-CCP antibodies.Compared to the subgroup of patients with RA seronegative (RF negative), only 2 patients have the highest titre of anti-CCP anti odies.The statistical analysis of the correlation between anti-CCP and RF in the group of patients with RA shows a very relevant statistical correlation (r=0,38)

3. Anti-CCP antibodies specificity was higher than that of RF, but the sensitivity was similar to that of RF. 4. Anti-CCP antibodies are markers of RA activity due to their statistically significant correlation with DAS, fibrinogen and C reactive protein.


5.

The correlation between anti-CCP antibodies and activity of RA was greater for moderately and highly increased titers of anti-CCP antibodies.6. Seropositive forms of RA had the highest seric titres of anti-CCP antibodies.7. Identifying the anti-CCP ant bodies in patients with RA is very useful in clinical practice not only as a diagnostic tool but also as a predictor of clinical outcome.8.The presence of the levels of anti-CCP antibodies may be an avail ble test in order to choose the suitable treatment for the patient with rheumatoid arthritis.

The authors consider that the problems presented in this study may be very useful for practitioners when dealing with patients with RA, taking into account the diagnostic and prognostic value of anti-CCP antibodies.Therefore, further clinical studies must be made so as to highlight the role of anti-CCP antibodies in RA.


Re

ntiatedpolya
thritis in patients with
© 2009, Carol Davila University Foundation
DiscussionsThe specificity of anti-CCP antibodies in our study was 90.56% and the sensitivity was 56.75%, as compared to medical literature where the specificiy of anti-CCP is 98% and the sensitiviy is 8